Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Team finds mechanism linking key inflammatory marker to cancer

21.05.2013
In a new study described in the journal Oncogene, researchers reveal how a key player in cell growth, immunity and the inflammatory response can be transformed into a primary contributor to tumor growth.

Scientists call this Jekyll-and-Hyde molecule NF-kappa B. In healthy cells, it is a powerful “first responder,” a vital part of the body’s immune and inflammatory responses. It spends most of its life in the cell’s cytoplasm, quietly awaiting orders.

But when extracellular signals – of a viral or bacterial invasion, for example – set off chemical alarms, the cell unchains this warhorse, allowing it to go into the nucleus where it spurs a flurry of defensive activity, including the transcription of genes that trigger inflammation, promote cell proliferation and undermine cell death.

Researchers have known for years that a hyperactive form of NF-kappa B that gets into the nucleus and stays there is associated with various cancers. But they didn’t know what was keeping it active in the nucleus.

“Normally in the cell NF-kappa B is in the cytosol, it’s not in the nucleus, and it’s not activated,” said University of Illinois medical biochemistry professor Lin-Feng Chen, who led the new study.

“You have to stimulate normal cells to see NF-kappa B in the nucleus. But in cancer cells without any stimulation you can see this nuclear form of NF-kappa B. The cell just won’t die because of this. That is why NF-kappa B is so important in cancer.”

In the new study, Chen’s group found that another molecule known to help regulate gene expression, called BRD4, recognizes a specific amino acid on a subunit of the NF-kappa B protein complex after the amino acid has been marked with a specific tag, called an acetyl group. This “acetylation” allows the BRD4 to bind to NF-kappa B, activating it and preventing its degradation in cancer cells.

Previous studies had shown that BRD4’s recognition of the acetylated subunit increased NF-kappa B activation, but this recognition had not been linked to cancer.

BRD4 belongs to a class of molecules that can recognize chemical markers on other proteins and interact with them to spur the marked proteins to perform new tasks. Chemical “readers” such as BRD4 are important players in the field of epigenetics, which focuses on how specific genes are regulated.

“In epigenetics, there are writers, there are readers and there are erasers,” Chen said. The writers make modifications to proteins after they are formed, without changing the underlying sequence of the gene that codes for them. These modifications (such as acetylation) signal other molecules (the readers) to engage with the marked proteins in various ways, allowing the proteins to fulfill new roles in the life of the cell. Epigenetic erasers remove the marks when they are no longer of use.

Such protein modifications “have been shown to be critically involved in transcription regulation and cancer development,” the researchers report.

To test whether BRD4 was contributing to the sustained presence of NF-kappa B in the nucleus of cancer cells, Chen and his colleagues exposed lung cancer cells in cell culture and in immune-deficient mice to JQ1, a drug that interferes with BRD4 activity.

Exposure to JQ1 blocked the interaction of BRD4 and NF-kappa B, blocked the expression of genes regulated by NF-kappa B, reduced proliferation of lung cancer cells and suppressed the ability of lung cancer cells to induce tumors in immune-deficient mice, the researchers found.

The researchers also discovered that depletion of BRD4 or the treatment of cells with JQ1 induced the degradation of the NF-kappa B subunit recognized by BRD4.

Chen said that BRD4 likely prevents other molecules from recognizing the hyperactive NF-kappa B in the nucleus and marking it for degradation.

“This is an example of how epigenetic regulators and NF-kappa B may one day be targeted for the treatment of cancer,” he said.

Researchers from Illinois biochemistry professor Satish Nair’s laboratory and from the laboratory of James Bradner at the Dana-Farber Cancer Institute contributed to this study.

Editor’s notes: To reach Lin-Feng Chen, call 217-333-7764;
email lfchen@illinois.edu.
The paper, “BRD4 Maintains Constitutively Active NF-''B in Cancer Cells by Binding to Acetylated RelA,” is available online or from the U. of I. News Bureau

Diana Yates | University of Illinois
Further information:
http://www.illinois.edu

More articles from Life Sciences:

nachricht Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

nachricht Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

Im Focus: How to inflate a hardened concrete shell with a weight of 80 t

At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).

Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...

Im Focus: Bacterial Pac Man molecule snaps at sugar

Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.

The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

Nothing will happen without batteries making it happen!

05.01.2017 | Event News

 
Latest News

Water - as the underlying driver of the Earth’s carbon cycle

17.01.2017 | Earth Sciences

Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

17.01.2017 | Materials Sciences

Smart homes will “LISTEN” to your voice

17.01.2017 | Architecture and Construction

VideoLinks
B2B-VideoLinks
More VideoLinks >>>